A recent study has unexpectedly pointed to the liver as the origin of Alzheimer’s plaques and not the brain, scientists from ModGene LLC and the Scripps Research Institute wrote in the Journal of Neuroscience Research. The authors say that their findings may completely change experts’ idea about the disease and how to treat and prevent it.
They used laboratory mice to determine which genes influence how much amyloid builds up in the brain. Three genes were found to protect mice from amyloid build-up and deposition. A lower expression of each gene in the liver protected their brains. One of the genes encodes presenilin – a protein found on the membrane of cells which researchers believe contributes towards Alzheimer’s development in humans.
Study leader, Professor Greg Sutcliffe, said:
“This unexpected finding holds promise for the development of new therapies to fight Alzheimer’s. This could greatly simplify the challenge of developing therapies and prevention.”
The authors explained that almost half of all Americans aged at least 85 years have Alzheimer’s disease. Approximately 5.1 million people in the USA are thought to be affected by it. By the middle of this century there should be between 11 million to 16 million people aged 65 and over in the country with the disease, unless new effective methods of treatment and prevention are found.
According to the Alzheimer’s Association, the cumulative costs of care for those with Alzheimer’s from 2010 to 2050 will be more than $20 trillion.
Sutcliffe and team have been on a genetic search-and-find mission, concentrating on naturally occurring, inherited differences in neurological disease susceptibility in different strains of laboratory mice. They have built up extensive databases and catalogued gene activity in different tissues, as measured by mRNA build-up. These data offer up maps of trait expression that can be superimposed on maps of disease modifier genes.
Scientists at Case Western Reserve had already mapped three genes that alter the accumulation of pathological beta amyloid in the brains of a transgenic laboratory mouse model of Alzheimer’s disease to large chromosomal regions. Each region has hundreds of genes. They used crosses between the B6 and D2 mice strains and studied over 500 offspring. Sutcliffe and team used those study findings and turned their own databases of gene expression to the Alzheimer’s mouse model. They were seeking out variations in gene expression that correlated in Alzheimer’s susceptibility between the B6 and D2 strains.
They had to create computer programs that identified each genetic variation that differentiated the B6 and D2 genomes, and then ran a regression analysis of each difference (a mathematical correlation analysis).
They made correlations between genotype differences between B6 and D2 and the quantity of mRNA product made from each of over 25,000 genes in a particular tissue in the 40 recombinant inbred mouse strains. They repeated the correlations 10 times to cover ten tissues, including the liver.
Sutcliffe said:
“A key aspect of this work was learning how to ask questions of massive data sets to glean information about the identities of heritable modifier genes. This was novel and, in a sense, groundbreaking work: we were inventing a new way to identify modifier genes, putting all of these steps together and automating the process. We realized we could learn about how a transgene’s pathogenic effect was being modified without studying the transgenic mice ourselves.”
Their gene quest offered up some good matches for each of the three disease modifier genes that the Case Western researchers had discovered. One of these matches (candidates) – “The mouse gene corresponding to a gene known to predispose humans carrying particular variations of it to develop early-onset Alzheimer’s disease.” – got Sutcliffe’s team especially interested.
Sutcliffe explained:
“The product of that gene, called Presenilin2, is part of an enzyme complex involved in the generation of pathogenic beta amyloid. Unexpectedly, heritable expression of Presenilin2 was found in the liver but not in the brain. Higher expression of Presenilin2 in the liver correlated with greater accumulation of beta amyloid in the brain and development of Alzheimer’s-like pathology.”
Their research indicated that considerable concentrations of beta amyloid likely start off in the liver and make their way to the brain through the bloodstream. If this can be confirmed, protecting the brain may be a achieved by simply blocking the production of beta amyloid in the liver.
The scientists set up an in-vivo experiment with wild-type mice – this type of mouse replicates the natural beta amyloid-producing environment more closely.
Sutcliffe said:
“We reasoned that if brain amyloid was being born in the liver and transported to the brain by the blood, then that should be the case in all mice, and one would predict in humans, too.”
The mice were given FDA-approved cancer drug Gleevec (imatinib), used for chronic gastrointestinal tumors and chronic myelogenous leukemia. It is known to lower the production of beta amyloid neuroblastoma cells. It also has poor penetration of the blood-brain barrier in mice and humans.
Sutcliffe said:
“This characteristic of the drug is precisely why we chose to use it. Because it doesn’t penetrate the blood-brain barrier, we were able to focus on the production of amyloid outside of the brain and how that production might contribute to amyloid that accumulates in the brain, where it is associated with disease.”
The mice were given Gleevec twice daily for seven days. Plasma and brain tissue were then collected, and they measured the amount of beta amyloid in the blood and brain.
,br> Gleevec was found to considerably lower beta amyloid levels not only in the blood, but also in the brain – remember, the drug cannot penetrate the brain. They concluded that much of the brain amyloid must start off outside the brain. Imatinib is a potential candidate for Alzheimer’s treatment and prevention, they added.
In order to move into clinical trials and new drug development Sutcliffe say he hopes to find a partner and backer.
J. Gregor Sutcliffe, Peter B. Hedlund, Elizabeth A. Thomas, Floyd E. Bloom, Brian S. Hilbush
Journal of Neuroscience Research: 3 MAR 2011 DOI: 10.1002/jnr.22603
Written by Christian Nordqvist